P667: RISK OF PROGRESSION IN CHRONIC PHASE-CHRONIC MYELOID LEUKEMIA PATIENTS ELIGIBLE FOR TYROSINE KINASE INHIBITOR DISCONTINUATION: FINAL ANALYSIS OF THE TFR-PRO STUDY
Authors: Giovanni Paolo Maria Zambrotta, Sarit Assouline, Franck E. Nicolini, Elisabetta Abruzzese, Ester Pungolino, Maria Cristina Miggiano, Chiara Elena, Alberto Alvarez Larran, Ana Triguero Moreno, Alessandra Iurlo, Cristina Bucelli, Francesca Lunghi, Isabella Capodanno, Margherita Maffioli, Sara Galimberti, Giovanni Caocci, Fabio Stagno, Susanne Saussele, Carmen Fava, Philipp Le Coutre, Massimiliano Bonifacio, Veronica Guglielmana, Federica Colombo, Laura Antolinni, Carlo Gambacorti-Passerini
Journal: HemaSphere (2023)

Background: Treatment discontinuation (TD) in patients (pts) with chronic phase (CP)-Chronic Myeloid Leukemia (CML) is recognized as one goal in the management of the disease. TD is generally safe, since MMR is achieved in almost all cases when TKI resumption is required. Disease progression (DP) to accelerated or blast phase (AP/BP) after TD was considered virtually impossible. However, recent reports documented at least 12 such cases, some of which fatal, raising safety concerns about TD. Aims: A quantification of the risk of DP in the setting of TFR has never been evaluated. The TFR-PRO study was designed to obtain a numerical assessment of the risk of DP in pts in deep molecular response (DMR) eligible for TD, regardless of their decision to attempt TD. Methods: This retro-prospective observational study enrolled CP-CML pts, followed at 20 centers in Italy, Canada, Germany, Spain, France. Pts eligibility included ≥4 years of TKI treatment and ≥18 months of stable DMR. The primary objective was to assess the risk of DP expressed as time adjusted rate (TAR) and its relationship to TD in CML pts who underwent TD. Pts eligible to TD who did not discontinue constituted the reference cohort. A flexible statistical approach allowed to attribute pts to the two groups according to their situation about TD (TD yes or no). Events developing in pts after the end of TD were considered associated to TD if they developed within 36 months since the end of TD. One secondary endpoint was the TAR of molecular relapse (MR, i.e. loss of MMR). Results: From July 24th, 2020 to November 10th, 2022, 907 pts were registered, of whom 870 were evaluable for the analysis (5152 person years). Median follow up was 5.5 years (IQR 2.6-8.6), median age at diagnosis was 50 years (IQR 40-61). Sokal score was low in 46.3%, intermediate in 34.8% and high in 18.9%. 505 pts (58%) attempted TD, 365 (42%) did not. MR occurred in 172/505 (34.1%) pts after TD, for a TAR of 11.8/100 person years (95% confidence interval (CI) [10.1-13.7]), but also in 64/365 (17.5%) pts of the reference cohort, for a TAR of 2.3/100 person years (95%CI [1.8-3.0]), p<0.0001. A representation of the estimated proportion of pts with MR is provided in the figure. Only one pt experienced DP to lymphoid BP, 55 after the end of TFR; he received BMT and is presently in remission. This event developed more than 36 months after MR, which was the protocol limit for considering an event linked to TD. Therefore, at the time of DP this pt was contributing to the reference cohort. Thus, the risk of DP was 1/870 or 0.1% (95% CI [0.0-0.6]) in the overall cohort, ranging from 0/505 or 0%, (95% CI 0.0-0.6%]) in the discontinuation cohort to 1/365 or 0.3% (95% CI [0.0-1.5%]) in the reference cohort. The TAR of DP was 0.019/100 person years (95%CI [0.003-0.138]) in the overall cohort, ranging from 0.0 (95%CI [0-0.002]) in the discontinuation cohort to 0.030 (95%CI [0.004-0.215]) in the reference cohort. The difference of this risk between the two cohorts is not statistically significant. Summary/Conclusion: These results indicate that pts who attempt TD have a significantly higher risk of MR than pts who do not. DP in pts eligible for TD is a rare event (approximately 1 in 1000 pts, or 0.019% per year in a single pt) and its relationship with TD is not demonstrated. It is important to underline that the pt experiencing DP had a very poor compliance to retreatment after the end of TFR, which contributed to the transformation of his CML. Therefore, when selecting pts for a TD attempt, emphasis should we given also to their willingness to resume TKI treatment in case of TD failure.Keywords: Blast crisis, Chronic myeloid leukemia, Progression, treatment-free remission